The specific aims of this grant proposal are to determine the consequences of paternal alcohol exposure on the outcome and development of their progeny. In several recent studies, we observed a number of behavioral and endocrinological abnormalities in the offspring of male rats who's fathers consumed alcohol during adolescence. In addition, we have observed a marked degree of tolerance to alcohol's effects and an enhanced sensitivity to other psychoactive drugs. These abnormalities in the offspring wee evident even though the amount of alcohol consumed by the fathers was only moderately intoxicating and despite the fact that breeding occurred following an extended alcohol-free period. The studies in this grant proposal will continue our analysis of the paternal effects of alcohol and address issues important for understanding the parameters involved and underlying mechanisms. Our specific aims are: First, to further characterize the deficits observed in male and female offspring of alcohol-exposed rats, including endocrinological and learning deficits. Second to examine in detail whether the acute sensitivity to alcohol and other psychoactive drugs, the development of tolerance and physical dependence on alcohol and other abused substances and the self selection of alcohol are altered in the offspring of alcohol-exposed fathers when compared to controls. Third, to determine whether the age of initial paternal exposure to alcohol is a critical factor in the deficits observed in their offspring (eg, does early exposure to alcohol produce greater deficits in subsequent offspring than does alcohol exposure in adults?). Fourth, to determine how much alcohol and over what duration is necessary to produce paternal alcohol effects on their offspring. Fifth, to determine whether the deficits observed in the offspring of alcohol-exposed male rats persist in subsequent generations resulting from breeding male and female alcohol- derived offspring. The proposed studies could have far-reaching clinical significance since alcohol abuse is increasing in adolescent boys and we know very little about the consequences of such abuse on their subsequent reproductive behavior, fertility and the outcome of their offspring. Moreover, in view of the findings that appears to be genetically linked to the fathers and that their sons appear to have significant physiological and behavioral deficits, it seems clear that the possibility of effects of paternal alcohol administration on fertility and fetal outcome should be explored. Based upon our preliminary data, our animal model may have unique clinical significance since the effects we have observed in the rat are similar to those found in the offspring of human alcoholic fathers: gender-specific cognitive and endocrine disturbances and differences in the sensitivity to alcohol challenges without evidence of gross malformation or severe developmental anomalies. The proposed studies could thus be instrumental in focussing on an important variable leading to birth defects and possibly the transmission of alcoholism.